Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but ...their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy-independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.
Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual ...resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and T
expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.
To compare changes in signal intensity (SI) ratios of the dentate nucleus (DN) and the globus pallidus (GP) to those of other structures on unenhanced T1-weighted magnetic resonance (MR) images ...between linear and macrocyclic gadolinium-based contrast agents (GBCAs).
The study was approved by the ethical committee of the University of Heidelberg (reference no. S-324/2014). Owing to the retrospective character of the study, the ethical committee did not require any written informed consent. Two groups of 50 patients who underwent at least six consecutive MR imaging examinations with the exclusive use of either a linear GBCA (gadopentetate dimeglumine) or a macrocyclic GBCA (gadoterate meglumine) were analyzed retrospectively. The difference in mean SI ratios of DN to pons and GP to thalamus on unenhanced T1-weighted images from the last and first examinations was calculated. One-sample and independent-sample t tests were used to assess the difference in SI ratios for both groups, and regression analysis was performed to account for potential confounders.
The SI ratio difference in the linear group was greater than 0 (mean DN difference ± standard deviation, 0.0407 ± 0.0398 P < .001; GP, 0.0287 ± 0.0275 P < .001) and significantly larger (DN, P < .001 and standardized difference of 1.16; GP, P < .001 and standardized difference of 0.81) than that in the macrocyclic group, which did not differ from 0 (DN, 0.0016 ± 0.0266 P = .680; GP, 0.0031 ± 0.0354 P = .538). The SI ratio difference between the last and first examinations for the DN remained significantly different between the two groups in the regression analysis (P < .001).
This study indicates that an SI increase in the DN and GP on T1-weighted images is caused by serial application of the linear GBCA gadopentetate dimeglumine but not by the macrocyclic GBCA gadoterate meglumine. Clinical implications of this observation remain unclear.
T2 relaxometry has become an important tool in quantitative MRI. Little focus has been put on the effect of the refocusing flip angle upon the offset parameter, which was introduced to account for a ...signal floor due to noise or to long T2 components. The aim of this study was to show that B1 imperfections contribute significantly to the offset. We further introduce a simple method to reduce the systematic error in T2 by discarding the first echo and using the offset fitting approach.
Signal curves of T2 relaxometry were simulated based on extended phase graph theory and evaluated for 4 different methods (inclusion and exclusion of the first echo, while fitting with and without the offset). We further performed T2 relaxometry in a phantom at 9.4T magnetic resonance imaging scanner and used the same methods for post-processing as in the extended phase graph simulated data. Single spin echo sequences were used to determine the correct T2 time.
The simulation data showed that the systematic error in T2 and the offset depends on the refocusing pulse, the echo spacing and the echo train length. The systematic error could be reduced by discarding the first echo. Further reduction of the systematic T2 error was reached by using the offset as fitting parameter. The phantom experiments confirmed these findings.
The fitted offset parameter in T2 relaxometry is influenced by imperfect refocusing pulses. Using the offset as a fitting parameter and discarding the first echo is a fast and easy method to minimize the error in T2, particularly for low to intermediate echo train length.
Abstract
Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. The exact nature and genesis ...of hypoxia-induced edema in healthy individuals remain unresolved. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI. This dual approach allowed us to directly measure key factors in the development of hypoxia-induced brain edema: (1) Sodium signals as a surrogate of the distribution of electrolytes within the cerebral tissue and (2) K
trans
as a marker of blood–brain–barrier integrity. The measurements point toward an accumulation of sodium ions in extra- but not in intracellular space in combination with an intact endothelium. Both findings in combination are indicative of ionic extracellular edema, a subtype of cerebral edema that was only recently specified as an intermittent, yet distinct stage between cytotoxic and vasogenic edemas. In sum, here a combination of imaging techniques demonstrates the development of ionic edemas following prolonged normobaric hypoxia in agreement with cascadic models of edema formation.
Objectives
To evaluate whether magnetic resonance imaging (MRI) can serve as an alternative diagnostic tool to the “gold standard” cone-beam computed tomography (CBCT) in 3D cephalometric analysis.
...Methods
In this prospective feasibility study, 12 patients (8 males, 4 females; mean age ± SD, 26.1 years ± 6.6) underwent 3D MRI and CBCT before orthognathic surgery. 3D cephalometric analysis was performed twice by two independent observers on both modalities. For each dataset, 27 cephalometric landmarks were defined from which 35 measurements (17 angles, 18 distances) were calculated. Statistical analyses included the calculation of Euclidean distances, intraclass correlation coefficients (ICCs), Bland-Altman analysis, and equivalence testing (linear mixed effects model) with a predefined equivalence margin of ± 1°/1 mm.
Results
Analysis of reliability for CBCT vs. MRI (intra-rater I/intra-rater II/inter-rater) revealed Euclidean distances of 0.86/0.86/0.98 mm vs. 0.93/0.99/1.10 mm for landmarks, ICCs of 0.990/0.980/0.986 vs. 0.982/0.978/0.980 for angles, and ICCs of 0.992/0.988/0.989 vs. 0.991/0.985/0.988 for distances. Bland-Altman analysis showed high levels of agreement between CBCT and MRI with bias values (95% levels of agreement) of 0.03° (− 1.49; 1.54) for angles and 0.02 mm (− 1.44; 1.47) for distances. In the linear mixed effects model, the mean values of CBCT and MRI measurements were equivalent.
Conclusion
This feasibility study indicates that MRI enables reliable 3D cephalometric analysis with excellent agreement to corresponding measurements on CBCT. Thus, MRI could serve as a non-ionizing alternative to CBCT for treatment planning and monitoring in orthodontics as well as oral and maxillofacial surgery.
Key Points
• Clinically established 3D cephalometric measurements performed on MRI are highly reliable and show an excellent agreement with CBCT (gold standard).
• The MRI technique applied in this study could be used as a non-ionizing diagnostic tool in orthodontics as well as oral and maxillofacial surgery.
• Since most patients benefiting from 3D cephalometry are young in age, the use of MRI could substantially contribute to radiation protection and open up new possibilities for treatment monitoring.
To compare multiparametric diagnostic performance with diffusion-weighted, dynamic susceptibility-weighted contrast material-enhanced perfusion-weighted, and susceptibility-weighted magnetic ...resonance (MR) imaging for differentiating primary central nervous system lymphoma (PCNSL) and atypical glioblastoma.
This retrospective study was institutional review board-approved and informed consent was waived. Pretreatment MR imaging was performed in 314 patients with glioblastoma, and a subset of 28 patients with glioblastoma of atypical appearance (solid enhancement with no visible necrosis) was selected. Parameters of diffusion-weighted (apparent diffusion coefficient ADC), susceptibility-weighted (intratumoral susceptibility signals ITSS), and dynamic susceptibility-weighted contrast-enhanced perfusion-weighted (relative cerebral blood volume rCBV) imaging were evaluated in these 28 patients with glioblastoma and 19 immunocompetent patients with PCNSL. A two-sample t test and χ(2) test were used to compare parameters.The diagnostic performance for differentiating PCNSL from glioblastoma was evaluated by using logistic regression analyses with leave-one-out cross validation.
Minimum, maximum, and mean ADCs and maximum and mean rCBVs were significantly lower in patients with PCNSL than in those with glioblastoma (P < .01, respectively), whereas mean ADCs and mean rCBVs allowed the best diagnostic performance. Presence of ITSS was significantly lower in patients with PCNSL (32% six of 19) than in those with glioblastoma (82% 23 of 28) (P < .01). Multiparametric assessment of mean ADC, mean rCBV, and presence of ITSS significantly increased the probability for differentiating PCNSL and atypical glioblastoma compared with the evaluation of one or two imaging parameters (P < .01), thereby correctly predicting histologic results in 95% (18 of 19) of patients with PCNSL and 96% (27 of 28) of patients with atypical glioblastoma.
Combined evaluation of mean ADC, mean rCBV, and presence of ITSS allowed reliable differentiation of PCNSL and atypical glioblastoma in most patients, and these results support an integration of advanced MR imaging techniques for the routine diagnostic workup of patients with these tumors.
The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and ...demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.
Objectives
To evaluate the accuracy and reliability of dental MRI for static guided implant surgery planning.
Materials and methods
In this prospective study, a 0.4-mm isotropic, artifact-suppressed, ...3T MRI protocol was used for implant planning and surgical guide production in participants in need of dental implants. Two dentists decided on treatment plan. Surgical guides were placed intraorally during a subsequent reference cone beam computed tomography (CBCT) scan. Inter-rater and inter-modality agreement were assessed by Cohen’s kappa. For each participant, dental MRI and CBCT datasets were co-registered to determine three-dimensional and angular deviations between planned and surgically guided implant positions.
Results
Forty-five implants among 30 study participants were planned and evaluated (17 women, 13 men, mean age 56.9 ± 13.1 years). Inter-rater agreement (mean κ 0.814; range 0.704–0.927) and inter-modality agreement (mean κ 0.879; range 0.782–0.901) were both excellent for the dental MRI-based treatment plans. Mean three-dimensional deviations were 1.1 ± 0.7 (entry point) and 1.3 ± 0.7 mm (apex). Mean angular deviation was 2.4 ± 1.5°. CBCT-based adjustments of MRI plans were necessary for implant position in 29.5% and for implant axis in 6.8% of all implant sites. Changes were larger in the group with shortened dental arches compared with those for tooth gaps. Except for one implant site, all guides were suitable for clinical use.
Conclusion
This feasibility study indicates that dental MRI is reliable and sufficiently accurate for surgical guide production. Nevertheless, more studies are needed to increase its accuracy before it can be used for implant planning outside clinical trials.
Key Points
• An excellent reliability for the dental MRI-based treatment plans as well as agreement between dental MRI-based and CBCT-based (reference standard) decisions were noted.
• Ideal implant position was not reached in all cases by dental MRI plans.
• For all but one implant site surgical guides derived from dental MRI were sufficiently accurate to perform implant placement (mean three-dimensional deviations were 1.1 ± 0.7 (entry point) and 1.3 ± 0.7 mm (apex); mean angular deviation was 2.4 ± 1.5°).
Brain metastases (BM) are an ever-increasing challenge in oncology, threatening quality of life and survival of many cancer patients. The majority of BM originate from lung adenocarcinoma, and stage ...III patients have a risk of 40–50% to develop BM in the first years of disease onset. As therapeutic options are limited, prevention of their occurrence is an attractive concept. Here we investigated whether Nintedanib (BIBF 1120), a tyrosine kinase inhibitor (TKI) targeting the VEGF pathway approved for lung adenocarcinoma, and the dual anti-VEGF-A/Ang2 nanobody BI836880 have the potential to prevent BM formation. A mouse model of brain metastasis from lung adenocarcinoma was used in which tumor cells were injected intracardially. Metastases formation occurred inside and outside of the brain and was followed by MRI, IVIS, and immunohistochemistry. BM were reduced in volume and number by both Nintedanib and the dual anti-VEGF-A/Ang2 nanobody, which translated into improved survival. Both compounds were able to normalize cerebral blood vessels at the site of brain metastatic lesions. Extracranial metastases, however, were not reduced, and meningeal metastases only partially. Interestingly, unspecific control IgG also lead to brain vessel normalization and reduction of brain and meningeal metastases. This data indicates a brain-specific group effect of antiangiogenic compounds with respect to metastasis prevention, most likely by preventing an early angiogenic switch. Thus, Nintedanib and BI836880 are promising candidates for future BM preventive study concepts in lung adenocarcinoma patients.
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